Our long-term goal is to understand the mechanisms of neurodegeneration in glaucoma and find new ways to abate it. Vision loss in glaucoma involves selective loss of retinal ganglion cell (RGC) neurons through two broad degenerative programs: in the optic projection, affecting RGC axons, and in the retina, affecting RGC dendrites, synapses and cell bodies. Degeneration arises from sensitivity to intraocular pressure (IOP), but IOP-lowering regimens do not always slow progression. Thus, to intervene at the neuronal level requires a better understanding of how the RGC pathway responds to IOP-related stressors and whether this response includes mechanisms to counter loss of function. Our objective in this project is focused on characterizing one such mechanism involving the TRPV1 (transient receptor potential vanilloid-1) receptor. Our central hypothesis is that TRPV1 counters RGC degeneration by enhancing excitatory activity in response to IOP- related stress. In other systems, increased TRPV1 at the neuronal membrane maintains cytoskeletal integrity and augments synaptic excitation by enhancing Ca2+ activity in response to stress. We propose a similar role for TRPV1 in RGCs, having established TRPV1 as a robust Ca2+ channel in RGCs that, when activated, increases excitation and influences their survival. We will test our hypothesis using both acute (microbead occlusion) and chronic (DBA2J) mouse models for which we have mapped key RGC degenerative outcome measures. For Aim 1, we will apply the acute model to a TRPV1 knock-out mouse to identify TRPV1- dependent axonal and retinal outcomes and their progression in RGC degeneration. For Aim 2, we will compare in the acute and chronic models IOP-dependent changes in TRPV1 expression and localization and link these changes to RGC subcellular compartments to identify structural correlates of TRPV1's action. For Aim 3 we will measure in both models how changes in IOP influence TRPV1's contribution to RGC excitation and determine if modulating TRPV1 sensitivity promotes survival. These new studies will capitalize on our completed studies of TRPV1 and a unique toolbox already in place to illuminate a novel cascade that could counter and slow stress-induced loss of function associated with glaucoma. PUBLIC HEALTH RELEVANCE: Glaucoma is the leading cause of irreversible blindness worldwide and will afflict an estimated 80 million people by 2020. The disease causes optic nerve degeneration through sensitivity to ocular pressure, but lowering pressure does not always stop progression. The work proposed here will test how a novel mechanism involved in pressure sensitivity might counter degeneration by enhancing nerve activity and whether this response represents a potential therapeutic opportunity.